Nonparallel nephrotoxicity dose-response curves of aminoglycosides

Abstract

Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Some high-dose studies in rats have also suggested that the slope of the nephrotoxicity dose-response curve of netilmicin was less steep than the slopes of other aminoglycosides. Therefore, the slopes of the nephrotoxicity dose-response curves of gentamicin, amikacin, and netilmicin were compared in 200 rats at low multiples (one to five times) of human clinical doses. Histopathological evaluations of both kidneys from each rat revealed that netilmicin produced equivalent or greater nephrotoxicity as compared with gentamicin and amikacin and that the slope of the nephrotoxicity dose-response curve of netilmicin was approximately one-half as steep as the slopes of amikacin and gentamicin, which were parallel. The distribution of casts excreted in the urine after 2 weeks of dosing and the terminal gross observations corroborated the flatter dose-response slope of netilmicin. Nephrotoxicity advantages predicted by high-dose comparisons with netilmicin in rats are apparently a function of its less steep dose-response slope and therefore may have no relevance to lower doses.When large multiples of the human dose of netilmicin are administered to rats, the drug is less nephrotoxic than gentamicin (2, 7, 10, 11, 13, 21), tobramycin (10,16,21), and amikacin (10), but netilmicin has appreciable nephrotoxicity in humans and cannot be differentiated from other aminoglycosides in clinics (1,15,20,22). Highdose toxicity comparisons in animals may be inappropriate for extrapolations to lower doses unless the slopes of their respective dose-response curves are linear and parallel (9). Comparative nephrotoxicity results with netilmicin in rats have suggested a relatively flat dose response at high multiples of the human dose (10, 21), although these studies did not employ sufficient numbers of dose levels to describe a nephrotoxic dose-response curve. Utilizing the dose-response model recently described (5), the nephrotoxicity dose-response curves of netilmicin, gentamicin, and amikacin were compared in rats at low multiples of the human dose. ( (Charles River Breeding Laboratories, Inc.) weighing between 75 and 100 g upon arrival were acclimated for 14 days before the initiation of this study. The rats were housed in individual cages of appropriate type and size in an environmentally controlled room and were given Purina Laboratory Rodent Chow and fresh drinking water ad libitum. Subsequently, the animals were ranked by body weight and randomly divided into groups of 10 before being individually identified by a tag number attached to an ear.Aminoglycoside administration. The doses (based on activity) were split and administered subcutaneously to the rats twice a day at approximately 9 a.m. and 3 p.m. Because of the differences in therapeutic doses, the daily doses of each amino...

Correlation between renal membrane binding and nephrotoxicity of aminoglycosides

“…These inhibitory potencies reflect the relative affinity of these aminoglycosides for the renal membranebinding site. The relative affinities are in good agreement with the in vivo nephrotoxic potentials of these aminoglycosides (14)(15)(16)30). Neomycin is consistently the most nephrotoxic aminoglycoside, whereas streptomycin is essentially nonnephrotoxic.…”

“…Amikacin affinity, as compared by Kd values, is approximately 100-fold lower in brush border membranes and 15-fold lower in basolateral membranes compared with gentamicin and netilmicin (18,19,42). The comparative renal membrane-binding affinities of amikacin, gentamicin and netilmicin correlate well with their nephrotoxic potentials (15).…”

“…High-dose comparisons in rats predicted a low nephrotoxic potential of netilmicin relative to other aminoglycosides (31). However, netilmicin has a shallow dose-response curve relative to other aminoglycosides, and when tested at low multiples of the human clinical dose, netilmicin nephrotoxicity was comparable to that of gentamicin (15). The clinical use of netilmicin has also been associated with appreciable nephrotoxicity (8, 37).…”

Differences in the Sensitivity of Fischer and Sprague-Dawley Rats to Aminoglycoside Nephrotoxicity

“…The lesions observed were identical to those previously described in similar aminoglycoside nephrotoxicity studies in rats (8,10,11,16). The lesions observed in F344 rats were similar to those observed in Sprague-Dawley rats but were quantitatively more pronounced.…”

Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats

“…The measure of kidney cortex DNA synthesis may also allow comparison of various aminoglycosides at low doses and after short-term administration, i.e., under conditions closer to those prevailing in the clinical use of these antibiotics. This is especially important since uptake of aminoglycosides by kidney cortex is dose saturable (14) and aminoglycosides do not always show parallel nephrotoxicity-dose-response curves (10).…”